In 1990, Gunasekera and co-workers at the Harbor Branch Oceanographic Institute reported the isolation of (+)-discodermolide (1), an architecturally novel metabolite of the marine sponge Discodermia dissoluta (0.002% w/w). (See, Gunasekera, et al., J. Org. Chem. 1990, 55, 4912. Correction: J. Org. Chem. 1991, 56, 1346).

Initial studies revealed that (+)-discodermolide suppresses both the two-way mixed-lymphocyte reaction and the concanavalin A-induced mitogenesis of murine splenocytes in vitro with no associated cytotoxicity. Moreover, (+)-1 suppresses the in vivo graft-vs.-host splenomegaly response induced by injection of parental splenocytes into F1 recipient mice, with potency intermediate between those of cyclosporin A and FK506. (Longley, et al., Transplantation 1991, 52, 650; Longley, et al., Transplantation 1991, 52, 656; Longley, et al. Ann. N.Y. Acad. Sci. 1993, 696, 94). These findings stimulated the recent discovery that (+)-1 arrests cell development at the M phase by binding and stabilizing mitotic spindle microtubules; thus discodermolide resembles taxol in its mode of action, but the microtubule binding affinity of 1 is much higher. (ter Haar, et al., Biochemistry 1996, 35, 243; Hung, et al., Chemi. & Biol. 1996, 3, 287). These and other results suggest that (+)-discodermolide holds considerable promise as an anticancer agent. The scarcity of natural material however has precluded a complete evaluation of its biological profile.
The absolute configuration of discodermolide remained undefined until Schreiber et al. synthesized both antipodes of 1. (Nerenberg, et al. J. Am. Chem. Soc. 1993, 115, 12621; Hung, et al., Chem. & Biol. 1994, 1, 67). Interestingly, the unnatural (−) antipode also displays significant immunosuppressant activity. Recently, the solution structure of (+)-Discodermolide has been reported as well as its conformation in DMSO. Smith, et al., “Solution Structure of (+)-Discodermolide”, Organic Letters, 2001, Vol. 3, No. 5, 695-698 and Montcagudo et al., “The Conformation of Discodermolide in DMSO”, J. Am. Chem. Soc., 2001, 123(28), 6929-6930.
Microtubules are believed to be required for a host of normal cellular processes, most importantly mitosis and cell division. When such a structure and its related biological functions are disrupted, cells can no longer undergo a normal cell cycle and eventually will die. Accordingly, microtubules have become a key target for cancer chemotherapeutic drugs with many diverse natural compounds targeting the tubulin/microtubule system.
Taxol, isolated from the Pacific Yew tree, has activity against a variety of human carcinoma cell lines and has been approved for the treatment of human breast, ovarian, and lung carcinomas. Rowinsky, E. K, “The development and clinical utility of the taxane class of antimicrotubule chemotherapy agents,” Annu. Rev, Med. 1997, 48, 353-374. In vitro, Taxol induces microtubule assembly in the absence of GTP that is normally required for assembly. Schiff, P. B., et al., “Promotion of microtubule assembly in vitro by Taxol,” Nature (Lond.) 1979, 277, 665-667. The resultant microtubules are stable against depolymerizing conditions such as cold temperatures or the addition of Ca2+. Thus, Taxol blocks cells in the mitotic phase of the cell cycle and causes microtubule bundling, ultimately leading to cell death. Schiff, P. B., et al., “Taxol stabilizes microtubules in mouse fibroblast cells”, Proc. Natl. Acad. Sci. USA, 1980, 77, 1561-1565; Jordan, M. A., et al., “Mitotic block induced in HeLa cells by low concentrations of paclitaxel (Taxol) results in abnormal mitotic exit and apoptotic cell death”, Cancer Res. 1996, 56, 816-825; Torres, K., et al., “Mechanisms of Taxol-induced cell death are concentration dependent”, Cancer Res., 1998, 58, 3620-3626. Even at low concentrations, the drug has a major effect on the dynamic instability of microtubules, reducing the dynamics dramatically. Jordan, M. A., et al., “Mechanism of mitotic block and inhibition of cell proliferation by Taxol at low concentrations”, Proc. Natl. Acad. Sci. USA, 1990, 90, 9552-9556; Derry, W. B., et al., “Substoichiometric binding of Taxol suppresses microtubule dynamics”, Biochemistry, 1995, 34, 2203-2211.
Other novel tubulin-stabilizing agents, such as the epothilones, eleutherobin, and (+)-discodermolide, have been identified. Bollag, D. M., et al., “Epothilones, a new class of microtubule-stabilizing agents with a Taxol-like mechanism of action”, Cancer-Res., 1995, 55, 2325-2333; Lindel, T., et al., “Eleutherobin, a new cytotoxin that mimics Paclitaxel (Taxol) by stabilizing microtubules”, J. Am. Chem. Soc., 1997, 119, 8744-8745; Ter Haar, et al., “Discodermolide, a cytotoxic marine agent that stabilizes microtubles more potently than Taxol”, Biochemistry, 1996, 35 243-250; Hung, D. T., et al., “(+)-Discodermolide binds to microtubules in stoichiometric ratio to tubulin dimers, blocks taxol binding and results in mitotic arrest”, Chem. Biol., 1996, 3, 287-293. These natural products have been isolated from a Myxobacterium fermentation, a marine soft coral, and a marine sponge, respectively. The new compounds appear to have a mechanism of action very similar to that of Taxol in that they promote the assembly of stable microtubules, and induce mitotic arrest and microtubule bundling in cells, although each with a unique potency. A number of structure-activity relationship (SAR) and modeling studies have been performed with Taxol, the epothilones, eleutherobin, and (+)-discodermolide in a search for a common pharmacophore model for these drugs. Winkler, J. D., et al., “A model for the Taxol (Paclitaxel)/epothilone pharmacophore”, Bioorg. Afed. Chem. Lett., 1996, 6, 2963-2966; Ojima, I., et al., “A common pharmacophore for cytotoxic natural products that stabilize microtubules”, Proc. Nati. Acad. Sci. USA, 1999, 96, 4256-4261; Wang, M., et al., “A unified and quantitative receptor model for the microtubule binding of Paclitaxel and epothilone”, Org. Lett., 1999, 1, 43-46; He, L., et al., “A common pharmacophore for Taxol and the epothilones based on the biological activity of a taxane molecule lacking a C-13 side chain”, Biochemistry, 2000, 39, 3972-3978; Giannakakou, P., “A common pharmacophore for epothilone and taxanes: molecular basis for drug resistance conferred by tubulin mutations in human cancer cells”, Proc. Natl. Acad. Sci. USA, 2000, 97, 2904-2909.
Although (+)-discodermolide was isolated and originally identified as a potential immunosuppressive agent, further studies revealed that the target of (+)-discodermolide was the microtubule system. Longley, R. E., et al., “Immunosuppression by discodermolide”, Ann. N.Y. Acad Sci., 1993, 696, 94-107; see, reports of Ter Haar, et al. and Hung, D. T., et al. noted above. For example, when compared to Taxol, (+)-discoderrnolide was found to be more potent at nucleating tubulin assembly and at inducing microtubule bundles in MCF-7 cells, and to have a higher affinity for tubulin. See report of Ter Harr, et al. noted above and Kowalski, R. J., et al., “The microtuble-stabilizing agent discodermolide competitively inhibits the binding of Paclitaxel (Taxol) to tubulin polymers, enhances tubulin nucleation reactions more potently than Paclitaxel, and inhibits the growth of Paclitaxel-resistant cells”, Mol. Pharmacol., 1997, 52, 613-622. In cells, however, (+)-discodermolide was less cytotoxic than Taxol. See Kowalski et al. noted above and Martello, L. A., et al., “Taxol and discodermolide represent a synergistic drug combination in human carcinoma cell lines”, Clin. Cancer Res., 2000, 6, 1978-1987. Moreover, it has been recently reported that Taxol and (+)-discodermolide represent a synergistic drug combination in human carcinoma cell lines, and as such may comprise a useful chemotherapeutic drug combination. See report of Martello noted above.
The scarcity of the natural product discodermolide (0.002% w/w from frozen sponge) has effectively precluded further development of this agent as a drug. It is therefore not surprising that discodermolide has attracted considerable interest from the synthetic community resulting in various synthetic approaches. Nerenberg, J. B., et al., “Total synthesis of the immunosuppressive agent (−)-discodermolide”, J Am. Chem. Soc., 1993, 115, 12621-12622; Smith, A. B., III, et al., “Total synthesis of discodermolide”, J Am. Chem. Soc., 1995, 117, 12011-12012; Harried, S. S., et al., “Total synthesis of discodermolide: an application of a chelation-controlled alkylation reaction”, J Org. Chem., 1997, 62, 6098-6099; Marshall, J. A., et al., “Total synthesis of (+)-discodermolide,” J Org. Chem., 1998, 63, 7885-7892; Halstead, D. P., “Total synthesis of (+)-miyakolide, (−)-discodermolide, and discodermolide”, PhD thesis, 1998, pp. 1-199, Harvard University, Cambridge, USA; Smith, A. B., III, et al., “Gram-scale synthesis of (+)-discodermolide”, Org. Lett., 1999, 1, 1823-1826; Paterson, I., et al., “Total synthesis of the antimicrotuble agent (+)-discomoderlide using boron-mediated aldol reactions of chiral ketones”, Angew. Chem. Int. Ed., 2000, 39, 377-380.
There is, therefore, both a need for improved synthetic methods for the preparation of discodermolide and compounds having similar chemical and/or biological activity as discodermolide.